PB2501: INSIGHT-1: A PHASE I FIRST-IN-HUMAN TCR TRIAL OF GENETICALLY MODIFIED T-CELLS TARGETING TDT IN CHILDREN AND ADULTS WITH T- AND B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA/LYMPHOMA (TRIAL-IN-PROGRESS)
Authors: Jochen Buechner, Even Holth Rustad, Saskia Meyer, Thea Gjerdingen, Eirini Giannakopoulou, Muhammad Ali, Ingerid Weum Abrahamsen, Anna Pasetto, Ying Yuan, Johanna Olweus
Journal: HemaSphere (2023)

Topic: 25. Gene therapy, cellular immunotherapy and vaccination - Clinical Background: Immunotherapy with chimeric antigen receptor (CAR) T-cells targeting CD19 (CD19 CAR-T) has revolutionized the curative treatment options for chemorefractory B-cell precursor acute lymphoblastic leukemia (B-ALL). However, around half of the patients relapse post CD19 CAR-T, and no CAR-T against T-cell ALL (T-ALL) has yet been approved. In contrast to a CAR, a natural T-cell receptor (TCR) can also target intracellular proteins, presented as peptides on HLA (MHC) molecules on the cell surface, vastly increasing the target repertoire. Our group has recently identified and characterized a TCR specifically recognizing a peptide derived from TdT (terminal deoxynucleotidyl transferase) presented on HLA-A*02:01 (Ali et al., Nat Biotech, 2022). TdT is expressed in most lymphoblastic malignancies. T-cells genetically modified to express the TdT-specific TCR efficiently eradicated B-ALL and T-ALL cells in vitro (primary leukemia samples from patients), and in vivo in advanced mouse models (PDX mice), if the leukemia cells expressed TdT and were HLA*02:01+. In contrast, HLA-A*02:01-negative or TdT-negative leukemia cells, as well as normal naïve and mature T-/B-cells and normal hematopoietic stem cells (naturally lacking TdT expression) were spared. Thymocyte development was unaffected in a humanized mouse model of normal hematopoiesis. Aims: InsighT-1 is a phase I/IIa first-in-human clinical trial to evaluate the safety, feasibility, pharmacodynamics and preliminary efficacy of autologous T-cells transduced to express the specific TdT-targeting TCR in patients aged ≥1 year with relapsed and/or refractory TdT+ B-/T-ALL or B-/T-LBL and who have no standard curative treatment option available, have evaluable disease at screening, are HLA-A*02:01+ (by HLA genotyping) and whose malignant cells express TdT (by immunohistochemistry and/or flow cytometry). Methods: The investigational product, TdT-3, consists of autologous CD8+-enriched T-cells retrovirally transduced to express the TdT TCR. TdT-3 will be manufactured on an automated CliniMACS Prodigy device at Oslo University Hospital, following a non-mobilized leukapheresis. After lymphodepleting chemotherapy with Flu/Cy, patients will be infused with fractionated doses of TdT-3, following a dose-escalation scheme with four dose levels. Dose escalation will be guided by the Bayesian optimal interval (BOIN) design. Primary endpoints are rate of successful provision (i.e. manufacture and release) of TdT-3 within a clinically relevant time frame (intent-to-treat), type, incidence and severity of dose limiting toxicities (DLT), and to establish the maximum tolerated dose (MTD), or highest dose infused if MTD is not reached, and recommended phase 2 dose (RP2D) of TdT-3. Secondary objectives include to determine the feasibility of manufacturing TdT-3 at the intended dose level, to evaluate the pharmacokinetics, pharmacodynamics and biodistribution of TdT-3, and to evaluate the preliminary efficacy of TdT-3. Results: Not yet available (trial-in-progress) Summary/Conclusion: InsighT-1 is a phase I/IIa dose-escalation trial (in-progress) evaluating a novel TCR immunotherapy targeting TdT in HLA-A*02:01+ patients with relapsed/refractory TdT+ T-/B-ALL or T-/B-LBL, which aims to enroll 15 patients over a 3-year period. Recruitment is planned to open in early 2024. Keywords: Adoptive immunotherapy, T-ALL, TCR, Clinical trial